The replicative cycle of lentiviruses such as HIV and SIV begins with the attachment of the virus to susceptible host cells, which is followed by fusion of viral and cellular membranes. These events are mediated by the exterior viral envelope glycoproteins and require the expression of the cellular receptor CD4 and a coreceptor, principally the chemokine receptor CCR5 or CXCR4. The HIV-1 envelope glycoprotein (Env) is a trimeric complex of heterodimers composed of a surface glycoprotein, gp120, and a transmembrane component, gp41. Virus association with CD4 triggers conformational changes in gp120 that promote high-affinity association with the coreceptor and expose helical region 1 (HR1) of gp41. The association of gp120 with CD4 and a coreceptor induces additional conformational changes in which gp41 helical regions 1 and 2 associate, placing viral and cellular membranes in close apposition and thereby promoting lipid mixing and viral fusion.
There have been some progresses in developing effective therapeutics (e.g., vaccines) that can afford protection against HIV infection, e.g., antibody-like immunoadhesins or broadly neutralizing antibodies (bNAbs). However, a large fraction of HIV-1 isolates remain partially or wholly resistant to even the best bNAbs. The immunoadhesin based therapeutics, e.g., CD4-Ig, were shown to neutralize most HIV isolates and irreversibly inactivate Env. However, the affinity of these therapeutics for Env are lower than those of bNAbs, and their potency is further compromised by its parallel ability to promote infection. Further, development of mimetics of the primary HIV-1 coreceptor CCR5 also did not lead to satisfactory HIV therapeutics.
There is a strong and urgent need in the art for more potent therapeutic compositions that can provide more effective and broad protection against infections of primate lentiviruses such as HIV. The present invention addresses this and other unmet needs in the art.